Activation and antitumor immunity of CD8 + T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid
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Le résumé fourni par la source
CD8 + T cell activation leads to the rapid proliferation and differentiation of effector T cells (T effs ), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8 + T effs , the mechanisms that regulate CD8 + T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8 + T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8 + T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8 + T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8 + T cells by directly binding to GLUT10’s intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8 + T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti–programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8 + T cells and identify that TME accumulated lactic acid inhibits CD8 + T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8 + T cell–mediated antitumor effects.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Activation and antitumor immunity of CD8 <sup>+</sup> T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid
- Date Crossref
- 28/08/2024
- Éditeur
- American Association for the Advancement of Science (AAAS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Chinese Academy of Medical Sciences & Peking Union Medical College State Key Laboratory of Bioactive Substance and Function of Natural Medicines pays non établi dans la noticeUniversité ou école supérieure
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Institute of Hematology & Blood Diseases Hospital pays non établi dans la noticeÉtablissement de santé
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Tongji University Department of Biochemistry and Molecular Biology pays non établi dans la noticeUniversité ou école supérieure
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Shanghai East Hospital pays non établi dans la noticeÉtablissement de santé
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Shandong University pays non établi dans la noticeUniversité ou école supérieure
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Chinese Academy of Medical Sciences and Peking Union Medical College State Key Laboratory of Bioactive Substance and Function of Natural Medicines pays non établi dans la noticeUniversité ou école supérieure
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Marine College pays non établi dans la noticeUniversité ou école supérieure
State Key Laboratory of Bioactive Substance and Function of Natural Medicines — Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Hematology & Blood Diseases Hospital et Department of Biochemistry and Molecular Biology — Tongji University, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.